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Rational Drug Design of Adenylation Enzyme Inhibitors

Recent evidence suggests that natural products are much more than simply agents of “microbial warfare” and actually play critical roles in bacterial pathogenesis and communication. In particular, non-ribosomal peptide (NRP) natural products have been identified as key players in bacterial iron uptake, biofilm formation, commensalism, and virulence. Thus, small molecule inhibition of NRP biosynthesis provides a powerful means to study the biological roles of these natural products and a potential avenue to develop novel antibiotics. Detailed mechanistic insights into NRP biosynthesis, developed primarily from the perspectives of fundamental interest and engineered biosynthesis, can be leveraged to design such inhibitors.

Salicyl-AMS, a novel adenylation inhibitor developed by rational drug design

In collaboration with Prof. Luis E. N. Quadri at Brooklyn College, we have developed a number of small molecule inhibitors of NRP biosynthesis using natural product-inspired mechanism- and structure-based design. These compounds target enzymes that catalyze key adenylation reactions in the biosyntheses of iron-chelating siderophores and mycobacterial phenolic glycolipids. Recently, in collaboration with Prof. William R. Bishai at Johns Hopkins, we have demonstrated the first in vivo antibacterial efficacy of one of these compounds, salicyl-AMS, in a mouse model of tuberculosis. In collaboration with Prof. Peter J. Tonge at Stony Brook University, we have also developed related inhibitors of menaquinone biosynthesis enzymes as a new class of potential antibiotics.

Crystal structure of the SUMO E1 enzyme with SUMO-AVSN, a chemical probe developed by rational drug design

Recently, in collaboration with Prof. Christopher D. Lima at MSKCC, we have used related strategies to develop semisynthetic, mechanism-based protein inhibitors of ubiquitin/ubiquitin-like E1 activation enzymes that regulate diverse biological processes in eukaryotes. This work has revealed striking conformational changes that occur during catalysis and provides new mechanistic insights that may be useful in drug discovery targeting these enzymes.

News Articles

06/01/2010Collaborative Team Advances the Understanding of an Important Activity Inside CellsMSKCC Center News
A collaborative team of researchers from Memorial Sloan Kettering has determined the mechanism for a biological process that plays a key role in regulating cellular behavior. The process — and the enzymes that control it — has been studied for 30 years, but until now it was a mystery to researchers in the field how this complex reaction takes place. [Full text]

02/22/2010Activation of Protein Tags: Enzymology: To prepare biological labels for attachment, E1 enzymes dramatically remodel themselvesChemical & Engineering News
In a tour de force chemical, structural, and mechanistic study that took five years, researchers have solved a long-standing mystery in a Nobel Prize-winning field of research-they have shown how E1 enzymes activate ubiquitin and related proteins to tag other proteins. [Full text]

02/18/2010Structural Biology: Transformative EncountersNature
Researchers have met the challenge of capturing transient states of the SUMO E1 activating enzyme. Their pictures show radically different crystal structures for two of the steps in this enzyme’s activity. [Full text]

08/18/2008From Peptides to Polymers: Molecular probes for biological investigationNYAS eBriefing
Chemical biologists seek to design new chemical tools for use in research and medicine. Their search is predicated on the incredible diversity of chemical structures, both natural and otherwise. This diversity was well represented at the Chemical Biology Discussion Group’s Special Year-End Meeting, held June 2, 2008.
[Overview (free) | Meeting report (membership req’d)]
Justin Cisar’s seminar: Inhibition of Nonribosomal Peptide Synthetase Amino Acid Adenylation Domains
[Video (membership req’d)]

01/01/2008A Novel Niche Approach to Antibacterial Drug DevelopmentStart-Up Magazine
Researchers are finding new ways to disable bacteria, either by increasing their sensitivity to existing drugs or decreasing their virulence. A group recently reported encouraging, if very early, results about the ability of an inhibitor of virulence factor biosynthesis to control tuberculosis infection. [Full text (subscription req’d)]

05/26/2005Chemical Biology: Ironing out bugsNature
Researchers from Cornell University and the Memorial Sloan Kettering Cancer Center in New York have devised a molecule that binds to and inhibits enzymes involved in siderophore synthesis. The compound successfully reduces the growth of both Mycobacterium tuberculosis and Yersinia pestis under iron-poor in vitro conditions. [Full text]